The overall aim of this study is to investigate the role of a common genetic polymorphism
in folate metabolism, MTHFR 677C→T, on blood pressure (BP) during pregnancy and the
impact of B-vitamin supplementation as a non-drug approach for the management of BP in
pregnancy in women with variant TT genotype.
Primary aims
To investigate BP in relation to MTHFR 677C→T polymorphism in pregnancy;
To investigate the response of BP during pregnancy to supplementation with
riboflavin (5mg/d) alone, or in combination with 5-MTHF (400μg/d), targeted at women
with the TT genotype;
Hypotheses:
BP will be higher in women with the TT genotype compared to those with CT and CC
genotype;
Targeted supplementation with riboflavin during pregnancy will prevent the greater
increase in BP observed in TT women compared to women with CC or CT genotypes;
Supplementation with riboflavin in combination with 5-MTHF maybe more effective in
preventing the greater increase in BP observed in TT women compared to women with CC
or CT genotypes;
Secondary aims
To examine the effect of maternal supplementation with riboflavin (5mg/d) alone, or
in combination with 5-MTHF (400μg/d), on BP of the offspring at 2-4 months and 3
years after birth in relation to this polymorphism;
To examine the relationship of riboflavin with haematological status and risk of
anaemia
To examine the effect of riboflavin supplementation on change in haemoglobin
concentrations
To evaluate the feasibility and acceptability of the study procedures to inform for
the required sample size and refinements of the study protocol (pilot phase).
Hypotheses:
Maternal supplementation with riboflavin, alone or riboflavin in combination with
5-MTHF, will influence the BP of newborns with TT genotype. In non-supplemented
mothers, newborns with the TT genotype will have higher BP compared to newborns with
CC and CT genotype. In supplemented mothers no genotype differences in newborns will
be observed.
Women with deficient biomarker status of riboflavin will have poorer haematological
status and will be at greater risk of developing anaemia during pregnancy.
Intervention with riboflavin will lead to improved haemoglobin concentrations
compared to placebo.
In advance of their first antenatal appointment, participants will receive a participant
information sheet from their obstetrician and those who are interested in the study will
be referred by the staff at antenatal clinics to the OptiPREG research team. At baseline,
pregnant women will provide a signed informed consent. Women with a singleton pregnancy
who are in their first trimester of pregnancy will be eligible to take part in the study.
Exclusion criteria will be: a high-risk pregnancy; a previous neural tube defect
(NTD)-affected pregnancy or being the first degree relative of a woman who had a
pregnancy affected with an NTD, or are themselves a sufferer of an NTD; use of medication
known to interfere with B vitamin metabolism (Chloramphenicol, Methotrexate, Metformin,
Sulfasalazine, Phenobarbital, Phenytoin, Primidone, Triamterene, Barbiturates). Those
women who are eligible to take part in the study will provide at baseline a buccal swab
to collect DNA for MTHFR genotyping, a non-fasting blood sample, and will have BP
measured, along with weight and height measurements and will complete a health and
lifestyle questionnaire and a 4-day food diary.
At 16th gestational week (GW), women with the TT genotype will be matched for age and
systolic BP to women with the CT and CC genotypes. Although the primary purpose of the
OptiPREG trial is to examine the effect of riboflavin intervention on BP in women with
the TT genotype, those with the CT genotype will be also randomised to intervention (in a
parallel trial). The purpose of this arm of the trial (in the CT genotype group) will be
to identify any potential foetuses with the TT genotype so that their BP, and the impact
of maternal B vitamin intervention, can be investigated. Within each genotype group (TT
and CT), women will be stratified by systolic BP and age and will be randomized to
receive 5 mg/day riboflavin, alone or in combination with 5-MTHF at 400µg/day, or
placebo, until the end of pregnancy. In order to encourage maximal compliance,
participants will be contacted regularly and provided with supplements in blister packs
every 6 weeks during the intervention, and will be asked to return the blister packs; the
number of unused capsules will be recorded to monitor compliance.
A second appointment will be organised at approximately the 36th GW when participants
will provide a second non-fasting blood sample, will have BP and weight measurements
taken and will provide information regarding any changes in health status, lifestyle and
medication usage.
Following delivery, cord blood sample will be collected; dimensions and the weight of
placenta will be measured, and placenta samples will be collected, together with a small
section of the umbilical cord. The weight and length of the newborn, as well as the type
of delivery and any complications in late pregnancy and birth will be retrieved from the
mothers records postpartum.
In parallel with the TT and CT women on intervention, age-matched pregnant women with the
CC genotype (not on intervention) will be monitored at the same time points (8-15 GW; 36
GW) in order to control for any changes in BP and other study outcome measurements
associated with normal pregnancy.
Mother-child pairs will be visited at home when the offspring are 2-4 and 36 months.
Weight, length and BP of the infant will be measured, and a buccal swab will be taken for
MTHFR genotyping. Maternal BP and weight will be measured and mothers will be asked to
provide information on health and lifestyle, infant feeding practice and health status.
Additionally, at the 3 year appointment, offspring neurodevelopment.
